The present invention relates in general to nonaqueous pharmaceutical compositions intended for use in aqueous physiological systems. More particularly, the present invention is directed to pharmaceutical compositions suspended in perfluorocarbons or fluorinated silicone liquids. The pharmaceutical compositions of the present invention possess unexpectedly superior shelf-lives, increased bioavailability, prolonged drug delivery profiles and may be configured for convenient multi-dose administration through common routes of pharmaceutical administration including advantageously small volume drop installation administration.
Pharmaceutical medicaments and diagnostic compounds are frequently incorporated into a delivery vehicle for administration to a targeted tissue site. Typically, drug delivery vehicles are formed as aqueous carriers, gels, polymeric material inserts or particulates incorporating a pharmaceutical compound. Once the drug delivery vehicle is placed at the desired delivery site, the pharmaceutical compound is released from the delivery vehicle over a prolonged length of time. The resulting time release profile of the drug is dependent upon a number of variables. Included in these variables are the release mechanism of the drug from the drug delivery vehicle (typically either erosion or diffusion), the amount of drug incorporated into the drug delivery vehicle, the solubility of the drug in the surrounding physiological milieu, and, in the case of particulate delivery vehicles, the particle size or size distribution of the vehicle.
Depending upon the physical characteristics of the vehicle itself as well as those at the intended target site, drug delivery vehicles may be delivered to the target site through a variety of known routes of administration. For example, aqueous based drug delivery solutions may be ingested, injected, inhaled, or applied directly to the skin or mucus membranes as drops, mists, or the like. Conversely, gels and ointments are better suited to direct topical application due to their relatively high viscosities. Similarly, solid polymeric inserts must be physically inserted or affixed to the target site.
A particularly unique target site for pharmaceutical compounds is the ocular environment surrounding the surface of the eye. Aqueous solutions, gels and solid inserts have all been utilized to deliver ocular drugs as the controlled delivery rate characteristics of such known delivery vehicles make them well suited for delivering therapeutic and diagnostic compounds to the ocular environment. However, tear turnover and drainage through the lacrimal system quickly remove a major portion of any compound administered as a drop to the eye so that only a small fraction of the original dosage remains in the eye long enough to be of therapeutic impact. Moreover, the unnecessarily high liquid dose volume inherent in water and oil based delivery systems results in inefficient use of the drug delivery compositions. Thus, repeated administrations of a drug formulated as an aqueous drop may be required to maintain an effective therapeutic level of the drug in the eye. Thus, pharmaceutical compositions such as ointments, gels or inserts which remain in the eye and gradually release their diagnostic or therapeutic drugs into the ocular environment reduce the need for repeated administrations of the drug to the eye.
Recently, drug delivery systems relying on drug microparticles, microcapsules or drug-containing erodible microparticles or microcapsules have been developed with some limited success. Such erodible microparticles or microcapsules are designed to be suspended in a liquid carrier medium and delivered to the target tissue through injection, ingestion or using liquid drops. Once at the target site the microparticulates or microcapsules are intended to remain at that location after the liquid carrier has diffused or drained away. Typically, microparticulates are formed of a drug or drug containing polymer matrix formed in particles ranging from tens to hundreds of microns in diameter. The polymer matrix may be erodible to release the incorporated drug at the target site as the matrix gradually breaks down. Alternatively, the microparticulates may be formed of non-erodible polymers from which the incorporated drug simply diffuses out of and into the target tissue. Microcapsules are comparably sized particles formed of a polymer shell encapsulating the desired pharmaceutical compound. The shell of microcapsules may also be composed of either erodible or non-erodible polymers.
The long term storage of microparticles and microcapsules requires a liquid carrier medium which is physically and chemically compatible with both the polymer of the drug delivery vehicle and the incorporated therapeutic or diagnostic compound as well as the intended physiologic environment. Generally, the liquid carrier of choice is a sterile water solution of the appropriate pH and osmolality. However, a problem with suspending micro-particles or microcapsules in aqueous carriers targeted for an aqueous physiological environment is that invariably the drugparticles will break down or dissolve or the polymer incorporated pharmaceutical compound will leach into the aqueous carrier prior to administration. This results in a significant loss of pharmaceutical activity at the site of action as the leached drug contained in the aqueous carrier will be flushed from the target site relatively rapidly.
The tendency of pharmaceutical compounds to breakdown or leach into the carrier also limits the effective shelf-life of drug delivery vehicles based upon aqueous carriers. Depending, upon the dissolution or diffusion rate of the incorporated pharmaceutical compound, the shelf-life will normally be much shorter than the preferred shelf-life. Similarly, diffusion of the drug into the aqueous carrier makes it difficult, if not impossible, to formulate pharmaceutical compounds into multiple dose packaging because uniform dose regimens cannot be ensured.
More specifically, pharmaceutical compositions containing drug delivery vehicles utilizing a polymer or drug which is unstable or labile in an aqueous environment cannot be stored for extended lengths of time in their aqueous carriers without significant chemical changes occurring. A significant number of the drugs and the polymers which are currently being utilized as microparticulate delivery vehicles are hydrolytically labile. This characteristic is central to the ability of the drug or polymer matrix to slowly disintegrate and to release the drug incorporated in the polymer matrix into the target aqueous physiological environment. Since the drug or polymer systems exhibiting hydrolytic instability cannot be stored in aqueous vehicles, they must be stored in a dry state and suspended in the aqueous carrier immediately prior to their administration to the target site. This is a time consuming and burdensome inconvenience to the end user. Moreover, it requires specialized packaging designs which provide a method for separately storing the labile drug or polymer particles and the carrier liquid in appropriate quantities. As a result, the package configuration must be limited to unit dose sizes with the attendant inconvenience and added costs.
Several nonaqueous liquid carriers have been utilized in the art in an attempt to address these problems. Among these are mineral oils, vegetable oils, silicone oils, and free fatty acids. Though generally effective for oral and dermal administration, when used in the ocular environment a significant disadvantage associated with these oils is that they combine with the lipid layer of the tear film which results in a disruption of the film. This in turn may cause the user to experience significant vision blurring and an unacceptable oily sensation. Even if the tear film is not disrupted, the significant difference in the refractive index of the tear film and the refractive index of the oil carrier causes blurring during the residence time of the oil.
A related drawback associated with the ophthalmic drop instillation delivery of pharmaceuticals incorporated in water or oil carrier systems is that conventional small volume droppers have relatively limited delivery volumes restricted to drop sizes that may interfere with vision or be uncomfortable to the user. This is because the density and surface tension characteristics of the typical water and oil based systems do not allow for the practical delivery of less than 35 xcexcl volumes. Thus, because the eye tear film can accommodate only about a 7 xcexcl volume of liquid, when amounts greater than this are delivered to the eye the excess liquid will disrupt the tear film and may be rapidly blinked away. This results in the inefficient and costly loss of both liquid carrier and pharmaceutical agent.
Accordingly, it is a principal object of the present invention to provide pharmaceutical compositions which will effectively deliver water labile or poorly soluble therapeutic or diagnostic pharmaceutical compounds to aqueous physiological target sites through a wide variety of administrative routes including ingestion, injection, inhalation, topical application, sprays, mists, drops and the like. It is a further object of the present invention to provide pharmaceutical compositions for delivering water labile or poorly soluble therapeutic or diagnostic pharmaceutical compounds which exhibit improved shelf-life and stability.
It is a further object of the present invention to provide drug delivering pharmaceutical compositions intended for use in aqueous physiological systems which maybe configured in multi-dose packages.
It is another object of the present invention to provide drug delivering pharmaceutical compositions capable of forming drop sizes on the order of 10 xcexcl generally a drop size greater than 1 xcexcl and less than 20 xcexcl, when delivered from standard dropper bottles.
It is also an object of the present invention to provide drug delivering pharmaceutical composition having improved efficiency of delivery.
It is an additional object of the present invention to provide pharmaceutical compositions containing hydrolytically labile polymers or drugs which are intended for use in aqueous physiological milieus which are protected from premature disintegration.
It is a further additional object of the present invention to provide effective pharmaceutical compositions which are transparent, nonirritating, and do not cause vision blurring when administered to the ocular environment.
The present invention accomplishes these and other objectives by providing advantageous pharmaceutical compositions formed of therapeutic or diagnostic compounds suspended in nonaqueous liquid carriers for low dose volume delivery. The pharmaceutical compositions of the present invention have improved bioavailability, provide efficient delivery of drugs in the form of low dose volumes and possess long shelf-lives with retained pharmaceutical activity and may be packaged in multi-dose configurations. Additionally, they can be formulated to stably incorporate hydrolytically labile drugs and polymers and may be administered to intended target sites through any available route of administration including small volume drop instillation methods. Unlike prior art drug delivery systems, the pharmaceutical compositions of the present invention can be delivered in dose volumes of greater than 1 xcexcl and less than 20 xcexcl, for example, 6 xcexcl to 12 xcexcl, and preferably greater than 1 xcexcl and less than 10 xcexcl, resulting in improved drug delivery efficiency and increased bioavailability.
In accordance with the teachings of the present invention, low volume pharmaceutical compositions are preferably formed from a perfluorocarbon or fluorinated silicone liquid carrier that may also contain a therapeutic or diagnostic compound and at least one drug delivery vehicle incorporating the desired therapeutic or diagnostic compounds. It is also contemplated as being within the scope of the present invention to form the drug delivery vehicle of polymeric particulates suspended in nonaqueous liquid carriers wherein the polymeric drug delivery vehicles incorporate a pharmaceutically effective amount of the desired therapeutic or diagnostic compounds. Preferably, the polymeric drug delivery vehicle is formed as a plurality of erodible microparticies or microcapsules which incorporate the compound of choice and are suspended in the nonaqueous liquid carrier. As those skilled in the art will appreciate, mixtures of differing erodible microparticles and microcapsules can be combined in a single carrier within the scope of the present invention to tailor the pharmaceutical composition to specific drug contents, polymer erosion rates, and drug release profiles.
Due to the nonaqueous character of the liquid carriers utilized in the pharmaceutical compositions of the present invention they are particularly suitable for suspending polymeric drug delivery vehicles prepared with hydrolytically labile polymers or pharmaceutical compounds. However, pharmaceutical compositions comprising hydrolytically stable polymeric drug delivery vehicles or pharmaceuticals are also within the scope of the present invention.
Unlike the prior art delivery systems, the pharmaceutical compositions of the present invention possess stable, long term shelf-lives without the associated loss of pharmaceutical activity of the therapeutic or diagnostic compound incorporated therein. This stability results from the fact that the therapeutic or diagnostic compound does not degrade, leach, or otherwise diffuse from the microparticulates or microcapsules into the liquid carrier, but remains stably incorporated in the drug delivery vehicle as compounded. Similarly, where the microparticulates or microcapsules are formed of water labile polymers, they will not erode or degrade in the compositions of the present invention.
Moreover, unlike prior art aqueous and oil based delivery systems, which are limited to a minimum of about 35 xcexcl drop sizes, the pharmaceutical compositions of the present invention form low volume doses of greater than 1 xcexcl and less than 20 xcexcl, for example, 6 xcexcl to 12 xcexcl, and preferably greater than 1 xcexcl and less than 10 xcexcl. The pharmaceutical compositions of the present invention may be packaged and sterilized by conventional gamma irradiation techniques. Sterile fill procedures are available as an alternative to radiation sterilizing techniques. Additionally, the pharmaceutical compositions can be configured for multiple or unit dose packaging from, for example, a dropper dispenser. The unique bacteriostatic properties of the liquid carriers further facilitate the utilization of multi-dose packaging by eliminating the necessity of preservative additives commonly used in the art.
As will be discussed below, a wide variety of polymers and therapeutic and diagnostic agents can be utilized in forming the compositions of the present invention. Polymers and agents which are hydrolytically labile are particularly suitable, however, the advantageous properties of the nonaqueous compositions can be obtained with hydrolytically stable drugs and drug delivery vehicles as well.
Further objects and advantages of the nonaqueous pharmaceutical compositions of the present invention, as well as a better understanding thereof, will be afforded to those skilled in the art from a consideration of the following detailed description of preferred exemplary embodiments thereof.